JP5581311B2 - MEDICAL DEVICE HAVING INORGANIC MATERIAL COATING AND MANUFACTURING METHOD THEREOF - Google Patents

Description

  The present invention relates to medical devices, and more particularly to medical devices having a coating containing a therapeutic agent.

  Many implantable medical devices are coated with a drug that is eluted from the medical device during implantation. For example, some vascular stents are coated with agents that are eluted from the stent for the treatment of blood vessels and / or to prevent some of the undesirable effects and complications in implanting the stent. In such drug-eluting medical devices, various methods have been proposed in order to realize a drug elution mechanism. However, there is a continuing need for improved devices and methods for achieving drug elution from medical devices.

  This application has been made in view of the above-mentioned concerns.

  In one aspect, the invention provides a medical device having a first form (eg, an unexpanded state) and a second form (eg, an expanded state), the medical device comprising (a) a reservoir containing a therapeutic agent And (b) a barrier layer disposed over the reservoir, the barrier layer comprising an inorganic material, wherein the barrier layer is against the therapeutic agent when the medical device is in the first configuration. Having a first transmittance and having a second transmittance for the therapeutic agent when the medical device is in the second configuration, the second transmittance is greater than the first transmittance.

  In another aspect, the present invention provides (a) a reservoir containing a therapeutic agent, (b) a barrier layer disposed over the reservoir and made of an inorganic material, (c) a barrier layer and the surface of the medical device And a swellable material, which is a material that swells when exposed to an aqueous environment.

  In yet another aspect, the present invention provides a medical device having a multilayer coating, the multilayer coating comprising: (a) a first reservoir layer that covers the surface of the medical device and is comprised of a first therapeutic agent; (B) a first barrier layer covering the first reservoir layer and made of a first inorganic material; (c) a second reservoir layer covering the first barrier layer and made of a second therapeutic agent; (D) a second barrier layer covering the second reservoir layer and made of the second inorganic material; and (e) a plurality of drilling regions penetrating over at least a partial thickness of the multilayer coating. .

  In yet another aspect, the present invention provides: (a) a polymer layer comprising a therapeutic agent and comprising a block copolymer; (b) comprising a inorganic material disposed over and covering the polymer layer; A medical device comprising a barrier layer having a continuous portion is provided.

  In addition, the present invention provides a method for forming a coating on a medical device and a method for delivering a therapeutic agent to a body site.

1 is a diagram of a stent according to one embodiment of the present invention. FIG. FIG. 3 is a top view of a strut on a stent. 1 is a diagram of a stent according to one embodiment of the present invention. FIG. 1B is a cross-sectional perspective view of a portion of the stent strut in FIG. 1A. FIG. 1 is a diagram of a stent according to one embodiment of the present invention. FIG. 1C is a cross-sectional side view of the stent strut in FIG. 1B before the stent is expanded. 1 is a diagram of a stent according to one embodiment of the present invention. FIG. 1C is a cross-sectional side view of the stent strut in FIG. 1B after the stent has been expanded. FIG. 6 is a cross-sectional view of a strut on a stent according to another embodiment. FIG. 6 is a view of a stent strut before the stent is expanded. FIG. 6 is a cross-sectional view of a strut on a stent according to another embodiment. Illustration of the stent strut after the stent has been expanded. FIG. 6 is a cross-sectional view of a strut on a stent according to another embodiment. Figure of stent strut after plug disassembly. FIG. 6 is a cross-sectional view of a strut on a stent according to yet another embodiment. FIG. 6 is a view of a stent strut before the stent is expanded. FIG. 6 is a cross-sectional view of a strut on a stent according to yet another embodiment. Illustration of the stent strut after the stent has been expanded. FIG. 6 is a cross-sectional view of a strut on a stent according to yet another embodiment. FIG. 6 is a view of a stent strut before the stent is expanded. FIG. 6 is a cross-sectional view of a strut on a stent according to yet another embodiment. Illustration of stent strut after stent is expanded. FIG. 6 is a cross-sectional view of a strut on a stent according to yet another embodiment. FIG. 6 is a view of a stent strut before the stent is expanded. FIG. 6 is a cross-sectional view of a strut on a stent according to yet another embodiment. Illustration of stent strut after stent is expanded. FIG. 6 is a cross-sectional view of a strut on a stent according to yet another embodiment. FIG. 6 is a view of a stent strut before the stent is expanded. FIG. 6 is a cross-sectional view of a strut on a stent according to yet another embodiment. Illustration of stent strut after stent is expanded. FIG. 6 is a cross-sectional view of a strut on a stent according to yet another embodiment. The stent strut before the water-swellable layer is hydrated. FIG. 6 is a cross-sectional view of a strut on a stent according to yet another embodiment. Figure of stent strut after water swellable layer is hydrated. FIG. 6 is a cross-sectional view of a strut on a stent according to yet another embodiment. Illustration of stent strut before the hydrogel capsule is hydrated. FIG. 6 is a cross-sectional view of a strut on a stent according to yet another embodiment. Illustration of stent strut after hydrogel capsule is hydrated. 6 is a cross-sectional view of a strut on a stent having a multilayer coating according to yet another embodiment. FIG. 6 is a cross-sectional view of a strut on a stent having a multilayer coating according to yet another embodiment. FIG. The enlarged view of the surface of a sputter deposition layer of gold. The figure of the atomic force microscope image of the surface of a SIBS block polymer film. FIG. 4 shows an example of a surface having feature elements (grooves) and feature regions (areas surrounded by grooves). FIG. 6 is a cross-sectional view of a strut on a stent according to yet another embodiment. Illustration of stent strut before dissolution of polymer layer. FIG. 6 is a cross-sectional view of a strut on a stent according to yet another embodiment. Illustration of stent strut after dissolution of polymer layer. FIG. 3 is an enlarged view of the surface of a sputter deposited gold layer with drug particles underneath. FIG. 16 is an enlarged view of the surface of the gold layer of FIG. 15 after additional sputter deposition of gold on the layer.

  In one aspect, the present invention provides a medical device having a first form and a second form. The medical device comprises a reservoir that contains a therapeutic agent. A barrier layer is deposited over the reservoir, and the barrier layer includes an inorganic material.

  The medical device may have various types of first and second configurations. In some cases, the medical device is an expandable medical device having an unexpanded configuration (first configuration) and an expanded configuration (second configuration). For example, the medical device may be an expandable stent or graft vessel that is delivered to a target body site in a non-expanded configuration and then expanded to an expanded configuration for implantation at the target site. In addition, various other types of first / second configurations are possible, including, for example, a non-bent / bent configuration, a non-stretched / extended configuration, or a non-deformed / deformed configuration.

  The reservoir containing the therapeutic agent may be provided in various ways. The reservoir may be the therapeutic agent formulation alone or may comprise a structure that holds or holds the therapeutic agent. For example, the reservoir may be a polymer layer or other layer that covers a medical device having a therapeutic agent disposed therein. In another example, the reservoir may be created in the surface of a medical device (eg, a porous surface) or the medical device may have pits, holes, cavities, or holes that contain a therapeutic agent.

  The barrier layer includes an inorganic material, which can be selected based on various considerations depending on the particular application. For example, an inorganic material has its biological properties (eg, biocompatibility), structural properties (eg, porosity), chemical properties (eg, chemical reactivity), handling properties (eg, storage stability), or deposition that can be used. The technology can be selected. Inorganic materials suitable for use in the barrier layer include pure metals including aluminum, chromium, gold, hafnium, iridium, niobium, palladium, platinum, tantalum, titanium, tungsten, zirconium, and alloys of these metals (eg, nitinol). And inorganic compounds such as metal oxides (eg, iridium oxide or titanium oxide), metal nitrides, and metal carbides, and inorganic silicides. Other suitable inorganic materials include some carbon-containing materials that have been previously studied, such as carbonized materials, carbon nanostructured materials (eg, carbon nanotubes, fullerenes, etc.) and diamond-like materials. It is.

  By being composed of an inorganic material, the barrier layer can be effective in improving the biocompatibility and therapeutic effectiveness of the medical device. For example, the barrier layer can be effective in preventing direct exposure of body tissue to a base polymer layer that is less biocompatible than the barrier layer. Furthermore, the barrier layer can provide a more attractive surface for body tissue. For example, in the case of vascular stents, the barrier layer can provide a surface that promotes endothelial cell migration and growth, which can help in reducing the occurrence of adverse effects associated with stent implantation.

  In some cases, the barrier layer can be formed utilizing any of a variety of layer deposition processes. For example, layer deposition processes that may be suitable for the formation of barrier layers include chemical vapor deposition, plasma vapor deposition, sputtering, pulsed laser deposition, sol-gel, deposition (thermal deposition, electron beam deposition, etc.), molecular beam epitaxy, solution A process (for example, spray coating, dip coating, roll coating, etc.) or electrodeposition (for example, electroplating, electrospray, etc.) is included. Further, the barrier layer can be formed by carbonization (eg, by laser heating or ion bombardment) of a precursor carbon material (eg, a polymer) to form a barrier layer formed from an inorganic carbonized material.

  The process utilized to form the barrier layer may be selected based on various considerations such as the type of medical device, the vulnerability of the therapeutic agent to thermal degradation, or the type of inorganic material used in the barrier layer. . The thickness of the barrier layer will vary depending on the particular application. In some cases, the thickness of the barrier layer ranges from 20 nm to 10 μm, but other thicknesses are possible.

  The barrier layer has a first transmittance for the therapeutic agent when the medical device is in the first configuration, a second permeability for the therapeutic agent when the medical device is in the second configuration, The transmittance of is higher than the first transmittance. Various possible degrees of transmission are possible for the first transmission and the second transmission of the barrier layer. In some cases, the first permeability does not achieve a therapeutically effective release profile of the therapeutic agent (eg, negligible or zero permeability), and the second permeability is therapeutically effective for the therapeutic agent. Realize the release profile. In some cases, the second transmittance is at least 1.5 times greater than the first transmittance, and in some cases at least 3.0 times greater than the first transmittance (first transmittance). Is not zero).

  The second transmittance is provided by a discontinuity formed in the barrier layer as the medical device changes from a first configuration (eg, an unexpanded configuration) to a second configuration (eg, an expanded configuration). As used herein, the term “discontinuity” refers to discrete defects in the barrier layer through which the therapeutic agent can travel through the barrier layer. Examples of such discrete defects include fracture lines, cracks, crevices, gaps, faults, holes, perforations, and other openings that penetrate the entire thickness of the barrier layer. These discontinuities may have a variety of dimensions and shapes, which can affect the transmittance of the barrier layer. For example, a relatively wide discontinuity can increase the permeability of the barrier layer and thus increase the rate at which the therapeutic agent diffuses through the barrier layer. The discontinuities can be linear or curved, jagged or smooth, irregular or regular, or have any of a variety of other patterns.

  In addition to providing a second transmission rate, these discontinuities may further serve to relieve stress on the adhesive bond between the barrier layer and the base substrate when the medical device undergoes deformation. By allowing discontinuities to be formed in the barrier layer, the barrier layer is less sensitive to strain and thus reduces stress on the adhesive bond when the medical device is subjected to deformation.

  In some embodiments, the medical device is provided in a first form (eg, an unexpanded form) where the barrier layer has a plurality of structurally weak regions. As used herein, “structurally weak region” refers to a relatively weak region in the barrier layer, and when the barrier layer is distorted, the discontinuity is this structurally weak. Formed and / or propagated in the region. In some embodiments, the structurally weak area is a drilling area in the barrier layer. As used herein, “excavation area” refers to a void (eg, hole, slot) created by removing material using techniques that control the size, shape, and position of the void. , Grooves, channels, etched parts, scribing lines, perforations, pits, etc.). For example, such techniques include direct write etching using an energy beam (eg, laser beam, ion beam, or electron beam), micromachining, microdrilling, or lithography processes.

  The excavation area may have various shapes and dimensions, which can be adjusted to achieve the desired amount of weakness in this particular area of the barrier layer. The excavation area may extend partially or completely through the barrier layer. By increasing the penetration depth of the excavation area, it is possible to increase the amount of weakness in this particular area of the barrier layer. In some cases, the drilling area has an average penetration depth of 10% to 90% of the total thickness of this layer, although other average penetration depths are also possible. In some cases, the average penetration depth of the excavation area is greater than 10% of the barrier layer thickness, in some cases greater than 33%, and in some cases greater than 50%. Furthermore, it is possible to increase the amount of barrier layer weakness in this particular area by increasing the width of the excavation area. In some cases, the excavation area has an average width in the range of 10 nm to 1 μm, although other average widths are also possible. The overall ratio between the surface area of the excavated area and the non-excavated area will vary depending on the particular application. In some cases, the excavation area may constitute 5-90% of the total surface area, and in some cases 30-70% of the total surface area, but other ratios may also be It is also possible. Furthermore, the surface area ratio of the excavation area to the non-excavation area may be different in different parts of the medical device.

  For example, referring to the embodiment illustrated in FIGS. 1A-1D, the struts 20 of the expandable stent 10 are coated with a polymer layer 30 containing a therapeutic agent. The polymer layer 30 is coated with a barrier layer 40 formed from iridium oxide. Referring to FIG. 1A, which shows a top view of a portion of the stent strut 20, the barrier layer 40 covering the stent strut 20 has a number of scribe lines 42 formed by laser etching. 1B is a cross-sectional perspective view of the portion 16 in FIG. 1A, and FIG. 1C is a cross-sectional side view of the portion 16 in FIG. 1A, where the barrier layer 40, polymer layer 30, And a stent strut 20 is shown. In this particular embodiment, the score line 42 partially penetrates the barrier layer 40.

  In use, the stent 10 is delivered to the body part in an unexpanded configuration. Upon reaching the target body site, the stent 10 is expanded. As illustrated in FIG. 1D, upon expansion, the deformation of the stent struts causes distortion in the barrier layer 40, resulting in the formation of cracks 44 in the barrier layer 40 along the score line. These cracks 44 allow the therapeutic agent to pass from the polymer layer 30 through the barrier layer 40 to the external environment.

  The laser used in the etching process may be any of a variety of lasers capable of ablating inorganic materials, including excimer lasers. Various parameters can be adjusted to achieve a desired result, including, for example, the wavelength of the laser, pulse energy, and / or pulse frequency. The laser can be applied using direct writing techniques or using masking techniques (eg, laser lithography). In some cases, cold ablation techniques are used (eg, using femtosecond lasers or short wavelength excimer lasers), which can reduce damage to the therapeutic agent or the polymer material in the medical device. When used, it can be effective in reducing damage to the polymeric material.

  In some embodiments, the drilling area may extend over the entire thickness of the barrier layer, and the drilling area is filled with a biodegradable packing material. For example, referring to the embodiment illustrated in FIGS. 2A and 2B, a stent strut 20 of an expandable stent is coated with a polymer layer 30 containing a therapeutic agent. The polymer layer 30 is coated with a barrier layer 50, which has a number of perforations 52. The perforations 52 are filled with a plug 54 that includes a biodegradable filler material such as a biodegradable polymer, a pharmaceutically acceptable salt or sugar, or a biodegradable metal (eg, magnesium).

  In use, the stent is delivered to the body site in an unexpanded state. Upon reaching the target body part, the stent is expanded. As illustrated in FIG. 2B, deformation of the stent struts causes strain in the barrier layer 50 when expanded. This causes the plug 54 to be partially separated or crushed, increasing the exposure of the plug 54 to physiological fluid. As illustrated in FIG. 2C, plug 54 then undergoes biodegradation such that perforation 52 is open. This allows the therapeutic agent to pass from the polymer layer 30 through the perforations 52 to the external environment.

  In some embodiments, the structurally weak regions are regions where the barrier layer has a thickness that is thin relative to the total thickness of the barrier layer. This thin region can be made in various ways during the formation of the barrier layer. In one example, a thin region can be created by placing a barrier layer over the textured surface, where the barrier layer is located over the protruding features of the textured surface, It has a thin thickness. The protruding features may be bumps, ridges, ribs, pleats, ridges, protrusions, ridges, highs, or other features that protrude from the textured surface. The textured surface may form a regular or irregular pattern.

  For example, referring to the embodiment illustrated in FIGS. 3A and 3B, the stent strut 20 of an expandable stent is coated with a polymer layer 32. The surface of the polymer layer 32 has a plurality of ridges 34. The polymer layer 32 is coated with a barrier layer 60. The portion of the barrier layer 60 that overlaps the ridge 34 is a relatively thin portion 62 that has a reduced thickness compared to the full thickness barrier layer 60.

  In use, the expandable stent is delivered to the body site in an unexpanded state. Upon reaching the target body site, the expandable stent is expanded. As illustrated in FIG. 3B, when the expandable stent is expanded, the deformation of the stent struts causes distortion in the barrier layer 60 and results in the formation of cracks 64 in the relatively thin portion 62 of the barrier layer 60. . These cracks 64 allow the therapeutic agent to pass from the polymer layer 30 through the barrier layer 62 to the external environment.

  Structurally weak areas can be distributed on various parts of the medical device in various ways. In some embodiments, the structurally weak areas are evenly distributed throughout the medical device. In some embodiments, the structurally weak regions in the barrier layer of a portion of the medical device have properties that are different from those of different portions of the medical device. In some cases, the structurally weak region allows a position-dependent variation in the strain force that the barrier layer will suffer when the medical device is changed from the first configuration to the second configuration, Deployed and / or constructed. For example, in the expandable stent 10 of FIG. 1A, as the stent 10 is expanded, various portions of the stent strut 20 will undergo various amounts of deformation. In this particular stent, the portion 12 of the stent strut 20 will undergo more deformation than the portion 14, resulting in greater strain in the barrier layer 40 covering the portion 12 than in the barrier layer 40 covering the portion 14. Thus, the structurally weak regions are made relatively weak in areas where the barrier layer 40 is subjected to relatively small strains, thereby providing the desired amount of second transmission in these areas of the barrier layer 40. It becomes possible to do.

  For example, referring to the embodiment illustrated in FIGS. 4A and 4B, the stent strut 20 of an expandable stent is coated with a polymer layer 30 containing a therapeutic agent. The polymer layer 30 is coated with a barrier layer 70. Referring to FIG. 4A, in the portion of the stent where the stent strut undergoes a relatively large deformation upon expansion, the barrier layer 70 has a shallow score line 72. Referring to FIG. 4B, in the portion of the stent where the stent strut undergoes a relatively small deformation upon expansion, the barrier layer 70 has a deep score line 74. In another example, referring to the embodiment illustrated in FIGS. 5A and 5B, a stent strut 20 of an expandable stent is coated with a polymer layer 30 containing a therapeutic agent. The polymer layer 30 is coated with a barrier layer 80. In addition, the shape of the base of the scribe line can have an effect on crack propagation, with blunt or relatively large diameter tips having lower stress concentrations than sharp or relatively small diameter tips. Endure. Thus, referring to FIG. 5A, the barrier layer 80 has a narrow score line 82 in the portion of the stent where the stent strut undergoes a relatively small deformation upon expansion. Referring to FIG. 5B, in the portion of the stent where the stent strut undergoes a relatively large deformation upon expansion, the barrier layer 80 has a wide score line 84. In yet another example, referring to the embodiment illustrated in FIGS. 6A and 6B, the stent strut 20 of an expandable stent is coated with a polymer layer 30 containing a therapeutic agent. The polymer layer 30 is coated with a barrier layer 90. Referring to FIG. 6A, in the portion of the stent where the stent strut undergoes a relatively large deformation upon expansion, the barrier layer 90 has a relatively low density score line 92. Referring to FIG. 6B, in the portion of the stent where the stent strut undergoes a relatively small deformation upon expansion, the barrier layer 90 has a relatively high density scribing line 92.

  In another aspect, the present invention provides a medical device having a reservoir containing a therapeutic agent. In addition, a barrier layer is disposed over the reservoir and the barrier layer includes an inorganic material. In addition, a swellable material is disposed between the barrier layer and the surface of the medical device, the swellable material being a material that swells when exposed to an aqueous environment. Such swellable materials include water swellable polymers and oxidizable metals. The composition and structure of the reservoir and the manner in which the reservoir can be formed are as described above. The composition and structure of the barrier layer and the manner in which the barrier layer can be formed are as described above.

  The barrier layer has a first permeability for the therapeutic agent before the swellable material swells and a second permeability for the therapeutic agent after the swelling material swells, the second permeability being the first permeability. 1 transmittance is exceeded. In some embodiments, the barrier layer may have structurally weak regions as described above. As the swellable material swells, it applies an outward pressure to the barrier layer. Discontinuities are formed in the barrier layer due to the strain applied by this pressure, thereby increasing the transmittance of the barrier layer. Therefore, the second transmittance of the barrier layer is realized by a discontinuity formed in the barrier layer when the swellable material swells. If the barrier layer has a plurality of structurally weak regions, the discontinuities may be formed in these regions.

  In some embodiments, the swellable material is a water swellable polymer that swells when hydrated. In such cases, the medical device is designed such that the water-swellable polymer is hydrated when the medical device is exposed to an aqueous environment (eg, body fluid or tissue). Aqueous fluids can be distributed to the water-swellable polymer via various routes. In some embodiments, the aqueous fluid can access the water-swellable polymer via a pathway that does not include a barrier layer. For example, the aqueous fluid may access the water-swellable polymer through another part of the medical device, or the aqueous fluid may be actively supplied to the water-swellable polymer by the medical device.

  In some embodiments, aqueous fluid from the outside environment accesses the water-swellable polymer by passing through the barrier layer, which is allowed by the first initial permeability of the barrier layer. This first initial transmission of the barrier layer may be realized in various ways. In some cases, the barrier layer may be porous or semi-permeable. In some cases, the barrier layer may have one or more initially present discontinuities that allow penetration of the aqueous fluid barrier layer. These initially existing discontinuities may be formed in various ways. One such method involves heating and / or cooling of the barrier layer, which causes thermal expansion and / or contraction of the barrier layer, resulting in the formation of discontinuities. For example, the barrier layer may be cooled by immersion of the medical device in a cold solvent mixture or a cryogenic liquid (eg, liquid nitrogen). In another example, the barrier layer may be subjected to alternating cycles of heating and cooling (or vice versa).

  Any of a number of different types of water-swellable polymers known in the art, including those that form hydrogels, may be used. Other examples of water swellable polymers include polyethylene oxide, hydroxypropyl methylcellulose, poly (hydroxyalkyl methacrylate), polyvinyl alcohol, and polyacrylic acid. The water swellable polymer may be applied to the medical device in various ways. For example, the water swellable polymer may be provided in the form of a gel, layer, fiber, aggregate, block, fine granule, particle, capsule, or sphere. In some cases, the water-swellable polymer is included in or under the polymer layer that contains the therapeutic agent. In such cases, the polymer layer can serve to control the rate at which the water-swellable polymer is hydrated.

  The following non-limiting examples further illustrate various embodiments of this aspect of the invention. In one example, referring to the embodiment illustrated in FIGS. 7A and 7B, a stent strut 20 of a stent is coated with a water swellable layer 100 formed from a hydrogel. Water swellable layer 100 is coated with a polymer layer 110 containing a therapeutic agent. The polymer layer 110 is coated with a barrier layer 120 that allows fluid to pass through the barrier layer 120 so that the water-swellable layer 100 can be hydrated when the stent is exposed to an aqueous environment. A plurality of small holes 122. In another embodiment, the positions of the water swellable layer 100 and the polymer layer 110 may be interchanged.

  In use, as the stent is delivered to the target body site, body fluid flows through the pores 122 in the barrier layer 120 and diffuses through the polymer layer 110 to hydrate the hydrogel in the water-swellable layer 100. As illustrated in FIG. 7B, the hydrogel hydration causes volume expansion of the water-swellable layer 100, thereby forming a crack 124 in the barrier layer 120. These cracks 124 allow the therapeutic agent to pass from the polymer layer 110 through the barrier layer 120 to the external environment.

  In another example, referring to the embodiment illustrated in FIGS. 8A and 8B, a stent strut 20 of a stent is coated with a polymer layer 114 containing a therapeutic agent. A capsule 102 containing a hydrogel is embedded in the polymer layer 114. The polymer layer 114 is coated with a barrier layer 130 that is semi-permeable to allow fluid to pass through the barrier layer 130.

  In use, body fluid flows through the semipermeable barrier layer 130, diffuses through the polymer layer 114, and hydrates the hydrogel in the capsule 102 as the stent is delivered to the target body site. As illustrated in FIG. 8B, hydration of the hydrogel causes volume expansion of the capsule 102, which in turn causes volume expansion of the polymer layer 114. This volume expansion of the polymer layer 114 results in the formation of cracks 132 in the barrier layer 130. These cracks 132 allow the therapeutic agent to pass from the polymer layer 114 through the barrier layer 132 to the external environment.

  In another embodiment, the swellable material is an oxidizable metal (eg, iron) that undergoes volume expansion upon oxidation. Oxidation can occur when exposed to an aqueous environment. Thus, the oxidizable metal can be used in a manner similar to that relating to the water-swellable polymer described above.

  In yet another aspect, the present invention provides a medical device having a multilayer coating. The multi-layer coating comprises a first reservoir layer that covers the surface of the medical device, the first reservoir layer comprising a first therapeutic agent. Furthermore, a first barrier layer is disposed over the first reservoir layer, and the first barrier layer includes a first inorganic material. In addition, a second reservoir layer is disposed over the first barrier layer, and the second reservoir layer includes a second therapeutic agent. These reservoir layers are formed using a material capable of holding or holding a therapeutic agent, such as a polymeric material.

  The first therapeutic agent and the second therapeutic agent may be the same or different. For example, in order to realize combination therapy, one therapeutic agent may be an antithrombotic agent and the other therapeutic agent may be an anti-inflammatory agent. Further, the various properties of the first reservoir layer and the second reservoir layer may be the same or different. Such properties include, for example, their composition, density, thickness, and the rate at which the therapeutic agent diffuses through the polymer layer. By individually controlling the properties of each reservoir layer, the release rate of the therapeutic agent can be adjusted.

  In addition, a second barrier layer is disposed over the second reservoir layer, and the second barrier layer includes a second inorganic material. The composition and structure of these barrier layers and the manner in which these barrier layers are formed are as described above. Each barrier layer may individually have its own various properties, including their composition, density, thickness, and permeability to therapeutic agents.

  Furthermore, a plurality of excavation areas (as defined above) penetrate through at least a partial thickness of the multilayer coating. The excavation area provides a means for allowing the therapeutic agent in the reservoir layer to be released into the external environment.

  For example, referring to the embodiment illustrated in FIG. 9, the stent strut 20 of the stent has a multilayer coating 170. The first layer in the multilayer coating 170 is a first reservoir layer 140 containing a first therapeutic agent. The first reservoir layer 140 is coated with a first barrier layer 150 that, in this particular embodiment, is impermeable to the first therapeutic agent. The first barrier layer 150 is coated with a second reservoir layer 142 that, in this particular embodiment, includes a second therapeutic agent that is different from the first therapeutic agent. The second reservoir layer 142 is coated with a second barrier layer 152 that is impermeable to the second therapeutic agent in this particular embodiment. A number of slots 160 that penetrate through the entire thickness of the multilayer coating 170 are created by laser ablation. In this particular embodiment, the slot 160 has a width in the range of 100 nm to 1 μm, although other widths are also possible depending on the particular application. In use, as the stent is delivered to the body site, the therapeutic agent diffuses from the reservoir layers 140 and 142 via the side surfaces (eg, side surfaces 146) of the reservoir layers 140 and 142. The therapeutic agent is then released from slot 160.

  The drilling area may have various shapes and dimensions, including various sizes, widths, shapes, and degrees of penetration of the multilayer coating. This feature may be effective in changing the release rate of the therapeutic agent. For example, referring to the embodiment illustrated in FIG. 10, the stent strut 20 of the stent has a multilayer coating 172 having slots (162, 164, 166, and 168) having a variety of different dimensions and shapes. The multilayer coating 172 includes a first reservoir layer 140 that includes a first therapeutic agent, a first barrier layer 150, a second reservoir layer 142 that includes a second therapeutic agent, and a second barrier layer 152. And have. Slot 162 partially penetrates multilayer coating 172 such that only reservoir layer 142 is exposed. With this shape, only the first therapeutic agent in the reservoir layer 142 is released from the slot 162. Further, slot 164 partially penetrates the multilayer coating, but both reservoir layers 140 and 142 are exposed. The slot 166 has a shape that is inclined with respect to the plane of the multilayer coating 172. Slots having this shape can be effective in spreading the side surfaces (eg, side surfaces 144) of reservoir layers 140 and 142, which increases the rate at which the therapeutic agent diffuses through these layers. Slot 168 has a wedge shape, which, like slot 166, expands the lateral surfaces of reservoir layers 140 and 142, thereby increasing the rate at which the therapeutic agent diffuses from these layers.

  In some embodiments, the excavation area of one part of the medical device has different characteristics than the excavation area of another part of the medical device. These different characteristics are possible due to different shapes or dimensions of the excavation area or different configurations (eg pattern, number or density). This feature may be effective in achieving different therapeutic agent release rates in different parts of the medical device or in releasing different therapeutic agents in different parts of the medical device. For example, a vascular stent has a larger or higher density drilling region at the end portion of the stent than at the middle portion of the stent to reduce undesirable “edge effects” that sometimes occur with stent implantation. It may be.

  The first barrier layer and the second barrier layer may have varying degrees of permeability to the therapeutic agent or may be completely impermeable. In some cases, the first barrier layer and / or the second barrier layer is impermeable so that the therapeutic agent is released only through the drilling region in the multilayer coating. The permeability of the barrier layer can be controlled in a variety of ways, including the choice of barrier layer thickness, density, deposition process utilized, and composition. By individually adjusting the permeability of the barrier layer, it is possible to further control the release rate profile of the therapeutic agent.

  In some embodiments, the multilayer coating comprises a plurality of alternating reservoir layers and barrier layers. For example, a third reservoir layer that includes a third therapeutic agent may be disposed over the second barrier layer, and a third barrier layer that includes a third inorganic material covers the third reservoir layer. It may be arranged.

  In yet another aspect, the present invention provides a medical device having a polymer layer, the polymer layer comprising a block copolymer and a therapeutic agent. In addition, a barrier layer is disposed over the polymer layer. The barrier layer includes an inorganic material and has a plurality of discontinuous portions. The composition and structure of the reservoir and the manner in which the reservoir can be formed are as described above. The composition and structure of the barrier layer and the manner in which the barrier layer can be formed are as described above.

  We have deposited (by sputter deposition) a thin layer of gold on a film of SIBS block copolymer on a stainless steel coupon, as illustrated at 60,000 times magnification in FIG. It was discovered that a nanometer-sized crack (approximately 20 nm width) was unexpectedly formed in the net pattern. This pattern of cracks in the gold layer is thought to follow the specific surface morphology of the SIBS polymer film. Referring to FIG. 12, the atomic force microscope image of the SIBS polymer film (deposited by vapor deposition on a stainless steel stent) has the surface morphology of this film as having features sized to about 30-90 nm. Show. These surface features are believed to be caused by the microphase separation region of the block copolymer in the film.

  Thus, in this aspect of the invention, the formation of the resulting discontinuities in the barrier layer allows release of the therapeutic agent in the polymer layer to the external environment, so that the polymer layer (block copolymer) And the barrier layer have a synergistic relationship. Furthermore, the resulting surface morphology of the barrier layer is believed to be capable of promoting endothelial cell attachment and / or growth, thereby enhancing the therapeutic effectiveness of medical devices implanted in blood vessels. Because it can be improved, the polymer layer and the barrier layer have a further synergistic relationship.

  In some embodiments, the surface morphology of the polymer layer comprises a plurality of microphase separation regions. In some cases, the surface morphology of the barrier layer follows the surface morphology of the polymer layer. In some cases, the discontinuities in the barrier layer follow the surface morphology of the polymer layer. Various properties of the microphase separation regions on the surface of the polymer layer (eg, their size, shape, and periodicity) depend on the specific properties of the block copolymer, such as the relative chain length, position, and composition of the block. Rely on. Thus, the block copolymer can be selected to achieve the desired surface morphology in the polymer layer, which in turn affects the formation of discontinuities in the barrier layer and / or the surface morphology. Become.

  In some embodiments, the surface morphology of the barrier layer comprises a plurality of feature elements or feature regions having a size that promotes endothelial cell attachment and / or growth. As used herein, the term “feature element” refers to any feature on a surface that renders the surface non-planar, non-smooth, or discontinuous. For example, the feature element may be a bump, a blob, a ridge, a granular part, a protrusion, a pit, a hole, an opening, a crack, a fracture line, a hole, a groove, a channel, and the like. As used herein, the term “feature region” refers to a region defined by one or more feature elements. For example, referring to the schematic diagram of FIG. 13, the surface 200 comprises a number of grooves 202 that define a series of pattern regions 204. The groove 202 is a considered feature element, and the pattern region 204 is a considered feature region. As used herein, the size of a feature element or feature region is intended to be measured along its shortest axis. In some cases, the feature element or feature region has an average size of less than 200 nm. In some cases, feature elements or feature regions have an average size in the range of 10 nm to 200 nm, and in some cases, an average size in the range of 30 nm to 90 nm. The pattern of feature elements or feature regions may be regular or irregular, ordered or random and may have various densities.

  In some embodiments, the polymer layer is exposed to a solvent that dissolves the polymer material in the polymer layer but does not dissolve the therapeutic agent. In some cases, the solvent can access the polymer layer through discontinuities in the barrier layer. For example, referring to the embodiment illustrated in FIG. 14A, a medical device 15 is coated with a polymer layer 180 formed from a block copolymer. The polymer layer 180 includes therapeutic agent particles 182. A barrier layer 190 is disposed over the polymer layer 180 and a crack 192 is formed in the barrier layer 190 due to the surface morphology of the polymer layer 180. The medical device 15 is then exposed to a solvent that penetrates through the crack 192 of the barrier layer 190 and dissolves the polymer material in the polymer layer 180. However, the therapeutic particles 182 are left intact. As illustrated in FIG. 14B, this results in the therapeutic agent being included in the polymer absent layer 184 below the barrier layer 190 in the coating. This feature can be effective in reducing exposure of body tissue to polymeric materials that cannot be fully biocompatible. In some cases, the barrier layer 190 may further be increased by further depositing additional inorganic material (eg, a biodegradable metal such as magnesium alloy, iron, or zinc) on the barrier layer 190. Good. The enhanced barrier layer 190 can be effective in reducing the permeability of the barrier layer 190 and thus in reducing the rate at which the therapeutic agent is released.

  In one experimental example, the coating was formed by sputter depositing a gold layer on top of a SIBS block copolymer film stainless steel coupon containing paclitaxel particles. The coating was then exposed to toluene, which penetrated through the cracks in the gold film and dissolved the SIBS polymer. FIG. 15 shows the surface of the gold layer (at 134,000 magnification), and the stored paclitaxel particles can be seen as bumps (black arrows) in the layer. Additional gold material was then sputter deposited over this coating to form the coating seen in FIG. 16 showing the surface at 60,000X magnification.

  Non-limiting examples of medical devices that can be used in connection with the present invention include stents, graft stents, catheters, guide wires, neurovascular aneurysm coils, balloons, filters (eg, vena cava filters), graft vessels, intraluminal Paving system, pacemaker, electrode, lead, defibrillator, joint implant, bone implant, spinal implant, access port, intra-aortic balloon pump, heart valve, suture, artificial heart, nerve stimulator, cochlear implant, retina Implants and other devices that can be used in connection with therapeutic coatings are included. Such medical devices include vasculature, gastrointestinal tract, abdomen, peritoneum, airway, esophagus, trachea, colon, rectum, biliary tract, prostate, brain, spinal column, lung, liver, heart, skeletal muscle, kidney, bladder, intestine Implanted in or otherwise used within body structures, cavities, or lumens, such as the stomach, pancreas, ovary, uterus, cartilage, eye, bone, and joint.

The therapeutic agent used in the present invention may be any pharmaceutically acceptable substance, such as a non-genetic therapeutic agent, a biomolecule, a small molecule, or a cell.
Exemplary non-genetic therapeutic agents include antithrombotic agents such as heparin, heparin derivatives, prostaglandins (including micelle prostaglandin E1), urokinase, and PPack (dextrophenylalanine proline arginine chloromethyl ketone); Anti-proliferative agents such as suprin, angiopeptin, sirolimus (rapamycin), tacrolimus, everolimus, zotarolimus, monoclonal antibodies capable of blocking smooth muscle cell proliferation, hirudin, and acetylsalicylic acid; dexamethasone, rosiglitazone, prednisolone, corti Anti-inflammatory agents such as costerone, budesonide, estrogen, estradiol, sulfasalazine, acetylsalicylic acid, mycophenolic acid, and mesalamine; paclitaxel, epothilone, Antineoplastic / antiproliferative / antimitotic agents such as radribine, 5-fluorouracil, methotrexate, doxorubicin, daunorubicin, cyclosporine, cisplatin, vinblastine, vincristine, epothilone, endostatin, trapidil, halofuginone, and angiostatin; c-myc Anticancer agents such as antisense inhibitors of oncogenes; antibacterial agents such as triclosan, cephalosporin, aminoglycoside, nitrofurantoin, silver ions, compounds or salts; biomembrane synthesis inhibitors such as non-steroidal anti-inflammatory agents, and ethylenediamine Chelating agents such as tetraacetic acid, O, O′-bis (2-aminoethyl) ethylene glycol-N, N, N ′, N′-tetraacetic acid and mixtures thereof; gentamicin, rifampin, minocycline, and Antibiotics such as lofloxacin; antibodies including chimeric antibodies and antibody fragments; anesthetics such as lidocaine, bupivacaine and ropivacaine; nitric oxide; phosphosidemine, molsidomine, L-arginine, NO-carbon adduct, NO adduct polymer or oligomer Nitric oxide (NO) donor; D-Phe-Pro-Arg chloromethyl ketone, RGD peptide-containing compound, heparin, antithrombin compound, platelet receptor antagonist, antithrombin antibody, antiplatelet receptor antibody, enoxaparin, hirudin Platelet aggregation inhibitors such as sodium warfarin, dicoumarol, aspirin, prostaglandin inhibitors, cilostazol, and anticoagulants such as tick antiplatelet factors; vascular cell formation such as growth factors, transcriptional activators and translational promoters Long promoter; growth factor inhibitor, growth factor receptor antagonist, transcription inhibitor, translation inhibitor, replication inhibitor, inhibitory antibody, antibody to growth factor, bifunctional molecule consisting of growth factor and cytotoxic, antibody and cytotoxic Vascular cell growth inhibitors such as bifunctional molecules consisting of; cholesterol-lowering agents; vasodilators; agents that interfere with endogenous vasoactive mechanisms; inhibitors of heat shock proteins such as geldanamycin; angiotensin converting enzyme ( ACE) inhibitors; beta blockers; βAR kinase (βARK) inhibitors; phospholamban inhibitors; protein-binding particle drugs such as ABRAXANE ™; structural protein (eg collagen) cross-linking disruptors such as Alagebrium (ALT-711); And any combinations and prodrugs of the above.

  Exemplary biomolecules include peptides, polypeptides, and proteins; oligonucleotides; antisense nucleic acids, such as double and single stranded DNA (including naked or cDNA), RNA, antisense DNA and RNA, low Molecular interference RNA (siRNA) and nucleic acids such as ribozymes; genes; hydrocarbons; angiogenic factors including growth factors; cell cycle inhibitors; and anti-restenosis agents. The nucleic acid can be incorporated into a delivery system such as a vector (including viral vectors), plasmid or liposome.

  Non-limiting examples of proteins include serca-2 protein, monocyte chemotactic protein (MCP-1), and, for example, BMP-2, BMP-3, BMP-4, BKMP-5, BMP-6 (VGR-1), BMP-7 (OP-1), BMP-8, BMP-9, BMP-10, BMP-11, BMP-12, BMP-13, BMP-14, BMP-15, etc. Forming protein ("BMP") is included. A preferred BMP is any one of BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, and BMP-7. These BMPs can be provided as homodimers, heterodimers, or combinations thereof, alone or with other molecules. Alternatively, or in addition, molecules capable of causing an upstream or downstream effect of BMP can be provided. Such molecules include any “hedgehog” proteins or DNA encoding them. Non-limiting examples of genes include survival genes that protect against cell death such as anti-apoptotic Bcl-2 family factors and Akt kinase; serca2 gene; and combinations thereof. Non-limiting examples of angiogenic factors include acidic and basic fibroblast growth factor, vascular endothelial growth factor, epidermal growth factor, transforming growth factors α and β, platelet derived endothelial growth factor, platelet derived growth factor , Tumor necrosis factor α, hepatocyte growth factor, and insulin-like growth factor. A non-limiting example of a cell cycle inhibitor is a cathepsin D (CD) inhibitor. Non-limiting examples of anti-restenosis agents include p15, p16, p18, p19, p21, p27, p53, p57, Rb, nFkB, and E2F decoy, thymidine kinase, and combinations thereof, and interfere with cell proliferation Other drugs useful for doing so are included.

Exemplary small molecules include hormones, nucleotides, amino acids, sugars, and lipids, and the compounds have a molecular weight of less than 100 kD.
Exemplary cells include stem cells, progenitor cells, endothelial cells, adult cardiomyocytes, and smooth muscle cells. The cells can be human (autologous or allogeneic) or animal (heterologous) or genetically engineered. Non-limiting examples of cells include side population (SP) cells, Lin ⁻ CD34 ⁻ , Lin ⁻ CD34 ⁺ , undifferentiated (Lin ⁻ ) cells including Lin ⁻ cKit ^+, and mesenchymal including 5-aza. Mesenchymal stem cells, including stem cells, cord blood cells, stem cells derived from heart or other tissues, whole bone marrow, bone marrow mononuclear cells, endothelial progenitor cells, skeletal muscle cells or satellite cells, muscle-derived cells, go cells, endothelial cells, Adult cardiomyocytes, fibroblasts, smooth muscle cells, adult cardiac fibroblasts + 5-aza, genetically modified cells, tissue engineering grafts, MyoD scar fibroblasts, pacing cells, embryonic stem cell clones, embryonic stem cells, Fetal or neonatal cells, immunologically masked cells, and teratoma-derived cells are included. Any therapeutic agent can be combined to the extent that the combination is biologically compatible.

  The polymeric material used in the present invention may comprise a biodegradable or non-biodegradable polymer. Non-limiting examples of suitable biodegradable polymers include polystyrene; polystyrene maleic anhydride; styrene-isobutylene-styrene block copolymers (SIBS) and styrene-ethylene / butylene-styrene (SEBS) block copolymers. Polyvinyl pyrrolidone including cross-linked polyvinyl pyrrolidone; copolymer of vinyl monomers such as polyvinyl alcohol and EVA; polyvinyl ether; aromatic polyvinyl; polyethylene oxide; polyester including polyethylene terephthalate; polyamide; poly (methyl methacrylate-butyl acetate Methyl methacrylate) Polyacrylamide containing block copolymers; Polyethers containing polyethersulfone; Polypropylene, Poly Polyethylenes including tylene and high molecular weight polyethylene; polyurethanes; polycarbonates, silicones; siloxane polymers; cellulose polymers such as cellulose acetate; polymer dispersions such as polyurethane dispersions (BAYHYDROL®); squalene emulsions; Any mixtures and copolymers are included.

  Non-limiting examples of suitable biodegradable polymers include polycarboxylic acids, polyanhydrides including maleic anhydride polymers; polyorthoesters; polyamino acids; polyethylene oxide; polyphosphazenes; polylactic acid, polyglycolic acid, And copolymers and mixtures thereof such as poly (L-lactic acid) (PLLA), poly (D, L-lactide), poly (lactic acid-co-glycolic acid), 50/50 (DL-lactide-co-glycolide); Polydioxanone; Polypropylene fumarate; Polydepsipeptide; Polycaprolactone and copolymers and mixtures thereof such as poly (D, L-lactide-co-caprolactone) and polycaprolactone co-butyl acrylate; polyhydroxybutyrate valerate and mixtures; tyrosine Origin polycar Polycarbonates such as acrylates and acrylates, polyiminocarbonates, and polydimethyltrimethyl carbonate; cyanoacrylates; calcium phosphates; polyglycosaminoglycans; (hyaluronic acid; cellulose and hydroxypropylmethylcellulose; gelatin; starch; dextran; alginates and their derivatives Macromolecules such as polysaccharides, proteins, and polypeptides; and mixtures and copolymers of any of the above. Biodegradable polymers are surface corrosive polymers such as polyhydroxybutyrate and its copolymers, polycaprolactone, polyanhydrides (both crystalline and amorphous), maleic anhydride copolymers, and zinc calcium phosphate. May be.

  The foregoing description and examples have been presented merely to illustrate the invention and are not intended to be limiting. Each of the disclosed aspects and embodiments of the invention can be considered individually or in combination with other aspects, embodiments, and variations of the invention. Those skilled in the art will recognize modifications of the disclosed embodiments that include the spirit and gist of the present invention, and such modifications are within the scope of the present invention.

  This application claims the priority of US Provisional Application No. 61 / 047,002, filed Apr. 22, 2008, the disclosure of which is incorporated herein in its entirety.

Claims (21)

A medical device,
A reservoir on the surface of the medical device, the reservoir containing a therapeutic agent;
A barrier layer disposed over the reservoir and made of an inorganic material;
A swellable material that is disposed between the barrier layer and the surface of the medical device and that swells when exposed to an aqueous environment;
Tona is,
The barrier layer has a first permeability to the therapeutic agent before the swelling of the swellable material, and has a second permeability to the therapeutic agent after the swelling of the swellable material. A medical device wherein the transmittance of 2 exceeds the first transmittance . The medical device of claim 1 , wherein the first transmittance is achieved by one or more discontinuities in the barrier layer. The medical device according to claim 2 , wherein further discontinuities are formed in the barrier layer by swelling of the swellable material. The medical device according to claim 1, further comprising an intermediate layer disposed between the medical device and the barrier layer, wherein the intermediate layer is made of a polymer material. The medical device according to claim 4 , wherein the intermediate layer includes the reservoir containing the therapeutic agent. The medical device according to claim 5 , further comprising a swellable layer disposed between the medical device and the barrier layer, wherein the swellable layer includes the swellable material. The medical device of claim 5 , wherein the intermediate layer further comprises the swellable material. The medical device of claim 7 , wherein the swellable material is contained within a capsule. The medical device of claim 1, wherein the barrier layer has a plurality of structurally weak areas. The medical device according to claim 1, wherein the swellable material is a water-swellable polymer . The medical device according to claim 1, wherein the swellable material is an easily oxidizable metal that swells during oxidation. The medical device according to claim 2 , wherein the one or more discontinuities are created by cooling the barrier layer. The medical device of claim 12 , wherein the barrier layer is cooled by exposure to a cryogenic liquid. Said one or more discontinuities, by at least one cycle heating and then cooling the barrier layer, or by at least one cycle of the barrier layer is then subsequently heating and cooling are produced, according to claim 2 Medical device. The medical device according to claim 1, wherein the medical device is a balloon. The medical device of claim 1, wherein the medical device is a stent. A method of forming a coating on a medical device according to any one of claims 1-16 , comprising:
Preparing a medical device;
Disposing a therapeutic agent over the surface of the medical device;
Covering the therapeutic agent and disposing a barrier layer made of an inorganic material;
Disposing a swellable material between the barrier layer and the surface of the medical device;
Removing a plurality of portions of the barrier layer to form structurally weak regions in the barrier layer;
A method that consists of: The method of claim 17 , wherein the removing is performed using an energy beam. The method of claim 18 , wherein the removing step is performed by laser ablation. The method of claim 17 , wherein the step of disposing the barrier layer comprises depositing the inorganic material over the therapeutic agent by a layer deposition step. 21. The method of claim 20 , wherein the layer deposition step is a nanoparticle deposition step.

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